Nilotinib is a potent and accurate second-generation tyrosine-kinase inhibitor, its application range includes an adult patient with a chronic myelogenous leukemia-chronic phase or accelerated phase treatment (including imatinib) history, and a drug-tolerant or intolerant Philadelphia chromosome of the patient is positive.
In existing researches, different synthesis methods for nilotinib are recorded in many patents and documents.
Route 1: in most of existing patents and documents, 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline is adopted as a raw material, and is coupled with 4-methyl-3-(4-(pyridine-3-yl) pyrimidine-2-ylamino)benzoic acid or a derivative thereof to obtain nilotinib.

R1 is H, and R2 is OH, Cl, alkoxy or aralkyl; or R1 is OH, and R2 is t-butyloxycarboryl.
Route 2: an arylcarboxylic acid is reacted with 3-bromo-5-(trifluoromethyl)aniline to produce amide, and the amide is further coupled with imidazole to obtain a target molecule nilotinib by a metal catalyst, wherein M is halogen or OH.

Route 3: 3-(pyridine-3-yl) pyrimidine-1-ylamine and substituted iodobenzene are coupled in the presence of a metal catalyst to obtain a target molecule nilotinib.

Route 4: amide is constructed by multiple steps, and then is coupled with a boric acid in the presence of a metal catalyst to obtain a target molecule nilotinib.

Route 5: 3-nitro-4-methylbenzoyl chloride is reacted with 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline, and substituted aryl guanidine is obtained by multi-step conversion, and then is coupled and condensed with an unsaturated ketone to obtain a target molecule nilotinib.

However, the above reaction routes also have some shortcomings: route 1 is excessively high in starting raw material cost, and each of routes 2 to 5 has lengthy synthetic sequences. Because an aromatic amine has poor nucleophilicity (compared with alkyl amines), a high temperature of over 120° C. is usually required when it is used for a palladium-catalyzed aminocarbonylation reaction, and consequently, it is necessary to increase carbon monoxide pressure, which increases a potential safety hazards. In addition, an application of a palladium-catalyzed carbonylation esterification/amination reaction to synthesis of pharmaceutical molecule containing numerous heteroatoms is limited. Since complexion of a nitrogen atom and a metal ion reduces a catalytic activity, a larger using amount of catalyst or a specially structured ligand is usually required to achieve a high yield in such a reaction, and these measures increase cost.
Based on the above problems, it is necessary to develop a novel route for synthesizing nilotinib, which is lower in cost and short in synthesis route.